Breast cancer accounts for about 23% of all cancers in women, and is the most common malignancy in the world. Mastectomy to remove affected breast tissue by surgery is a frequently adopted treatment option. Seroma formation, which refers to accumulation of fluid in vivo after surgery, is a common complication.
Incidence of seroma formation after mastectomy may reach maximally 53%, and may cause many complications including infection, flap necrosis, and delayed wound healing, which brings huge sufferings to the patients. It is believed that the dead space between the skin and adjacent tissues results in seroma formation.
Conventional methods against seroma formation include tacking down the skin flap and placement of drains at the surgery site. Each of these methods suffers from limitations. For example, the tacking method may be effective to close the auxiliary dead space, but may perform poorly to prevent seepage from the transaction.
Placement of drains presents the route for bacterial invasion due to their invasive nature, and may easily result in deep wound infection. Moreover, use of suction drainage may increase chance of flap necrosis and peripheral nerve damage. Gluing of the skin flap and adjacent tissues together with tissue adhesive, so as to physically close up the auxiliary dead space for seroma formation, is considered an effective strategy to prevent seroma formation.
Currently available tissue adhesives, such as fibrin glue, cyanoacrylate adhesives, or glutaraldehyde-based adhesives, have been successfully used for hemostasis and open/skin wound sealing. There are, however, still no suitable tissue adhesives for large-area in vivo usage such as seroma prevention.
An ideal tissue adhesive for large-area in vivo applications should be (1) safe and non-toxic, (2) rapidly cross-linkable, and (3) possess long-term effectiveness in physiologically wet environments. For instance, as constituents of fibrin glue (fibrinogen and thrombin) are from blood, use of fibrin glue inevitably runs the risk of blood-mediated pathogen transmission. As another example, cyanoacrylate- or glutaraldehyde-based adhesives have exhibited acute and/or chronic toxicity.
Many adhesives, sealants, and haemostats have been developed and approved by US Food and Drug Administration (FDA), as shown in TABLE 1.
TABLE 1FDA-approved tissue adhesives, sealants, and haemostatsAdhesives/Product BrandsIndicatedSealants(Chemical name)ApplicationsProsConsFibrinTisseel andAs an adjunctFast curing.TransferringGlueEvicel (Humanhemostat inBiocompatibility.risk of blood-pooled plasmasurgery.Biodegradability.borne disease.fibrinogen andAs an adjunctRisk ofthrombin).for the closureallergicVitagel andof colostomies.reaction.Cryoseal systemVitagel is usedRisk of(Autologousas an adjunctinfectionplasmahemostat duringtransmission.fibrinogen andsurgicalLongthrombin).procedures.preparationCryoseal systemtime.is used as anPoor tissueadjunctadhesion.hemostat onExpensive.liver resection.Ancillaryequipmentrequired.AlbuminBioGlueAs an adjunctFast crosslinking.Toxicity ofand(Bovinehemostat forGood adhesion toglutaraldehyde.Glutaraldeserum albuminstandardtissue.hydeandmethods (such10%as suture andglutaraldehyde)staple) in opensurgical torepair largevessels.CyanoacrylatesDermabond (2-Closure ofFastExothermicOctyltopical skin.polymerization.crosslinking.cyanoacrylate)ConjunctionStrong adhesionProlongedIndermil (n-with but no inRelativelydegradation.Butyl-2-deep dermalinexpensive.Toxicity ofcyanoacrylate)stitches.degradationHistoacryl andClosure ofproducts.Histoacryl Blueskin wounds.Limited to(n-Butyl-2-Skin closuretopical uses.cyanoacrylate)in endoscopicincisions.Poly(ethyleneCoseal (four-Sealing sutureRapid gelRisk ofglycol)armedlines andformation.swelling.(PEG)PEGs, cappedvascular graft.Biocompatibility.PossiblebasedWith glutaryl-Sealing ofFast hemostasis.allergicsealantssuccinimidylcerebrospinalreaction.ester or the otherfluid.Relativelywith thiols, andexpensive.dilute solution ofhydrogenchloride andsodiumphosphate-sodiumcarbonate)Duraseal (PEGester powder andtrilysine aminesolution withFD&C blue No. 1dye).
All the substances listed are commercially available, and have been used in surgeries. None of the products is, however, competent for large-area in vivo applications such as seroma prevention, although fibrin glue and Bioglue were once considered promising candidates.
Fibrin glue contains fibrinogen and thrombin, both of which come from blood and bears risk of infection contamination. Due to the weak bonding strength and fast degradation of fibrin glue, its current applications are to control bleeding, during or after surgeries. Bioglue is composed of bovine serum albumin and 10% glutaraldehyde. Recent studies have shown that use of glutaraldehyde in vivo is associated with some diseases such as cancer and leukemia.
Further examples of adhesives, sealants, and haemostats are provided in TABLE 2, where limitations, such as complicated synthesis and long cure time, are present.
TABLE 2Further examples of adhesives, sealants, and haemostatsChemicalIndicatedAdhesion andcomponentApplicationscure timeProsCons3,4-Bond of porcine155 kPa andStrongLong curedihydroxyphenylalanineskin and12 hoursadhesiontimeand L-lysineporcine boneBiocompatibilityComplicatedsynthesisNeed hightemperature,vacuum andorganic solventExpensiveFour-armImmobilizeNo reportedFastComplicatedpoly(ethylenetransplantedadhesion andcrosslinkingsynthesisglycol), 3,4-islet20-30dihydroxyhydrocinnamicsecondsacid andsodium periodateCitric acid, PEG,Wounds closure123 kPa andBiocompatibilityNondegradableand dopaminetwo hoursComplicatedsynthesisNeed hightemperature andvacuumRelativelyexpensiveExtracted adhesiveNo reported57-462 kPaFastExpensiveprotein fromapplicationand severalcrosslinkingmarine musselssecondsBiocompatibility(Mytilus edulis)and metal ionsV5+, Fe3+ and Cr6+Peptide Fmoc-Wound closure30.4 kPa andFastComplicatedAla-Ala-OH,two hourscrosslinkingsynthesisbranchedNeed organicpoly(ethylenesolventglycol) (PEG), andRelativelysodium periodateexpensivePolyethyleneHernia repair168-357 kPaStrongComplicatedglycol (PEG),and twoadhesionsynthesispolycaprolactonehoursNeed organic(PCL), N—Boc-solventGly-OH, 3,4-Relativelydihydroxyhydrocinnamicexpensiveacid, andsodium periodateHyaluronic acid,Drug and cell7.18 kPa andBiocompatibilityComplicateddopamine, anddeliveryno reportedsynthesisthiolated Pluroniccure timeExpensiveF127 copolymerGelatin extractedHemostat ofNo reportedBiocompatibilityComplicatedfrom humanhemorrhagingadhesion andFast gelationpreparationadipose tissue,livercure ininstable intyrosinase, andsecondsvivoFeCl3 solutionExpensiveChitosan, thiolatedHemostat of20.8 kPa andBiocompatibilityComplicatedPluronic F-127,hemorrhaging48 hourssynthesisand hydrocaffeicliverExpensiveacidThiolated 3-armedSkin closureAbout 11 kPaFast gelationNondegradablepoly(ethyleneand 10Complicatedglycol), 3,4-minutessynthesisdihydroxy-L-phenylalanine, N-hydroxysuccinimideester, andacrylic acid
In view of the above, there exists a need for an improved biological tissue adhesive that overcomes or at least alleviates one or more of the above-mentioned problems.